Front-line therapy with pembrolizumab doubled progression-free survival (PFS) compared with chemotherapy in patients with microsatellite instability–high (MSI-H) mismatch repair– deficient (dMMR) metastatic colorectal cancer (mCRC) during the KEYNOTE-177 trial, according to results presented at the 2020 virtual annual meeting of the American Society of Clinical Oncology (abstract LBA4).
The Merck-funded study involved 307 patients with MSI-H or dMMR mCRC who were randomly assigned 1:1 to receive standard-of-care chemotherapy or pembrolizumab (Keytruda, Merck). Standard-of-care regimens consisted of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) with or without bevacizumab or cetuximab.
Investigators led by Thierry AndrÉ, MD, of the Sorbonne UniversitÉ and HÔpital Saint Antoine, in Paris, reported that median PFS was 16.5 months in the pembrolizumab group and 8.2 months in patients receiving standard of care (hazard ratio, 0.60; P=0.0002). At 12 and 24 months of follow-up, PFS was 55.3% and 48.3%, respectively, with pembrolizumab versus 37.3% and 18.6%, respectively, with standard of care.
Of patients receiving pembrolizumab, 11% experienced a complete response (CR), 32.7% had a partial response (PR) and 20.9% had stable disease. In comparison, 3.9%, 29.2% and 42.2% of patients receiving standard of care had a CR, PR and stable disease, respectively.
In addition, response was more durable with pembrolizumab, with 83% of patients having a response lasting longer than two years, compared with 35% of patients receiving chemotherapy.
Grade 3 or greater treatment-related adverse events (AEs) were less common with pembrolizumab than chemotherapy (22% vs. 66%). Immune-mediated AEs (colitis and hepatitis) were more common with pembrolizumab, whereas the most frequent chemotherapy-related AEs in the standard-of-care group were diarrhea, neutropenia, fatigue, nausea and vomiting, stomatitis, alopecia and neurotoxicity.
“This is a paradigm-changing study,” said Cindy L. O’Bryant, PharmD, a professor in the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora. “For our MSI-H metastatic colorectal patients, this provides a potential first-line treatment option that doesn’t contain chemotherapy. That is huge because the side effects of standard-of-care colorectal cancer chemotherapy regimens can be debilitating and impactful on patient quality of life and tolerability.”
According to Dr. O’Bryant, based on the results of the trial, if a patient has MSI-H mCRC, a good performance status, right-sided disease and is KRAS wild type, pembrolizumab should be strongly considered as first-line treatment. “For patients who don’t meet that criteria, the advantages of pembrolizumab in this setting are less clear,” Dr. O’Bryant said.
“Despite the significant increase in PFS and durable responses, the benefit of pembrolizumab in this study was not seen until after six months,” she added. “Until we know more, it is important that patients be individually assessed to determine optimum front-line therapy.”
Dr. AndrÉ reported financial relationships with Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Clovis Oncology, GIC Advice, Gristone Oncology, GSK/Tesaro, HalioDx, MSD Oncology, Pierre Fabre, Roche, Sanofi, Servier and Ventana. Dr. O’Bryant reported financial relationships with GSK/Tesaro and Pfizer.
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